Professor, Orthopedic Surgery, Stanford University
Associate
Director, Sports Medicine, Stanford University Hospital and
Clinics, Redwood City, California
Relaxation and chronic stress alleviation herbals vs pharmaceuticals purchase himplasia 30caps line, beneficial exposure to natural allergens and microbes greenridge herbals order himplasia 30caps otc, and enhanced physical activity are some of hypothesized pathways to these salutogenic effects aasha herbals buy 30caps himplasia otc. It has been hypothesized that enhancing contacts with natural living environment in urban settings can enhance innate resilience to detrimental effects of environmental stressors including air pollution herbals interaction with antihistamines order himplasia 30 caps without prescription. Allostatic load estimates are based on multiple biomarkers of immune herbals during pregnancy purchase himplasia 30 caps visa, metabolic and neuroendocrine functions herbals india chennai generic 30 caps himplasia with visa. These associations persisted after adjusting for traffic air pollution levels and body mass index suggesting that likely pathways to health were stress mitigation and immune system modulation. Other studies demonstrated that exposure to air pollution can affect the same biomarkers in the opposite direction. Thus, this pilot study contributed to a growing body of evidence that contacts with the living nature reduce vulnerability to environmental insults including air pollution. A larger ongoing study with an expanded set of immune system biomarkers includes analysis of gut microbiome to assess links between residential greenness, microbiome, and immune function. A prospective component of this study aims to evaluate if reduced allostatic load increases resilience to short-term environmental insults. Available species-specific in vivo toxicokinetic data were used for model calibration and independent datasets were used for model validation. Critical determinants governing tissue distribution were determined by local sensitivity analyses. Simulation results suggest that the model predictions were successfully validated across species with estimated residual error of less than 2-fold. Dopamine neurons were especially sensitive, exhibiting evidence of neurotoxicity at doses below the toxicity threshold for other neurotransmitter systems (as low as 75 ppm). People residing in Kentucky and surrounding states may face higher exposures due to nearby manufacturing. While previous studies have been conducted to investigate their toxicities, exact toxic mechanisms remain unclear. Cryostax 5-donor pool of cryopreserved human hepatocytes were cultured following manufacturer protocols and certified reagents. After a 48 hr treatment, gene expression of lipogenic targets related to steatosis were determined using a custom QuantiGene 2. Further studies will evaluate gene and lipid endpoints of hepatocytes from normal donors and donors with steatosis. A low sample size (n=3 per dose) pilot postnatal study at 125 mg/kg/d was largely negative for adverse effects but indicated potential reductions in female body weight and reduced weights of male reproductive tissues in F1 animals. This study is ongoing with evaluation of adult F1 animals that were exposed in utero. Evaluation of in vitro assay performance is required to use high-throughput data for predictive toxicology. Assay performance is typically assessed using reference chemicals-compounds with defined activity or inactivity against the test system target. However, developing reference chemical lists has historically been resource-intensive and context specific. We developed a semi-automated workflow for selecting and annotating reference chemicals across many targets in a standardized format. Activity information was extracted into a database, using automated scripts, from multiple public sources including non-curated scientific literature and curated chemical-biological databases, resulting in the identification of chemical activity in 2995 molecular targets. The sample data from literature sources covering 54 molecular targets ranging from data-poor to data-rich were manually reviewed for accuracy. This overall approach allows rapid development of candidate reference chemical lists for a wide variety of targets that can facilitate performance evaluation of in vitro assays as a critical step in imparting confidence in alternative approaches. Data extraction of author reported health findings have introduced a data consistency and semantic challenge because terms reported by authors are inconsistent. The results (between the input [author term] and Bioportal ontology classes) were scored as: 1 = perfect match, 0. Drug discovery has historically relied on the massive screening of compound libraries with in vitro cell-based target assays. These techniques, generating thousands of data points per day, require standardized and robust data analysis procedures that can enable a rapid decision-making process. The effects of seven chemical constituents present in tobacco or tobacco smoke on normal human bronchial cells are reported as use case: three metals (arsenite, mercury, and selenite), two phenols (phenol and p-cresol), acrylamide, and naphthalene. The severity scores rank metals as more toxic than phenols and assign low severity to acrylamide and naphthalene. National Library of Medicine and the herbal monograph of the European Medicines Agency. Other relevant data were collected from governmental documents, public databases, web sources, and the literature. Benchmarks indicated that the prediction accuracy was improved beyond the 95% confidence intervals of existing models. Asthma rates in California have shown an increase in counties with extensive use of the pesticide permethrin. Notably the surrounding agricultural area of Imperial County reports significant asthma related admissions to the emergency room per year. In separate studies, the most frequent users of permethrin were more likely to report wheeze, both allergic and non-allergic during medical exams, and there exists suggestive evidence of wheeze associated with permethrin exposure among children. This study utilizes online databases, docking software, data networks, predictive molecular modeling software and literature to identify a potential chemical-gene-disease link between permethrin exposure and asthma. Induction of these pathways can be attributed, in part, to ligand binding of estrogen receptors found on the surface membrane of various immune cells within the alveolar and pleural cavities. Deep machine learning methods have emerged as powerful techniques to extract knowledge from large amounts of data. In this work, a big set of chemicals (17,008) with their Ames mutagenicity outcomes was utilized to build deep neural network models and evaluate their predictive performance. The conventional model is highly interpretable because it is composed of fragment-based alerts that were mined directly from the training data. They pose special difficulties across the board for traditional machine learning and classification algorithms. Yet, the future of big data is now, equating to some urgency in finding approaches for overcoming the challenges of analyzing sparse datasets. In this study we developed the Neighbor-Edges Based and Unbiased Leverage Algorithm (Nebula) to tackle sparse big data. ToxCast data have been studied to characterize the toxicological profiles of environmental chemicals. We found that the chemical-assay network could be decomposed into seven densely connected modules based on its topological properties. Our study demonstrated Nebula to be an efficient algorithm for analyzing sparsely populated big data and, thus, useful in the big data era. Our results also indicated ToxCast data could be used for toxicologically profiling chemicals that have not been assayed in ToxCast to assist risk assessment of chemicals. A novel method of substituting taxonomy groups for species dummy variables was introduced to allow the model to generalize to other species. A stacked ensemble of three machine learning methods-random forest, gradient boosted trees, and support vector regression-was implemented to increase accuracy with minimal feature selection. In animal free risk assessments, in vitro effect concentrations need to be related to external. In conclusion this demonstrates the applicability of the applied concept in general, the need for its future optimization and allows us to derive questions on what we need to know to further optimize these calculations. Current methods for estimating the health risks of chemicals require guideline animal testing studies. Only a small fraction of chemicals possesses adequate data for assessing potential hazards. This fact highlights the urgent need to develop more efficient and informative toxicity determination tools. In vitro high-throughput screening assays combined with computational models might provide a suitable alternative to traditional animal testing studies. The aim of the present study was to model the plasma and hepatic pharmacokinetics of approximately 50 disparate types of chemicals and drugs after virtual oral administrations in rats based on reported rat plasma values and experimental pharmacokinetics determined after oral administration to rats. To ensure the diversity of chemical structures in the original chemical space, the chemical structures described by 196 chemical descriptors were calculated by a chemoinformatics tool using 50,000 randomly obtained molecules. The resulting chemical space was then projected onto a two-dimensional plane for visualization using generative topographic mapping methods. This study provides important information to help simulate the high hepatic levels of potent hepatotoxic compounds. The present models could estimate the relationships between plasma/hepatic concentrations of chemicals and drugs after oral doses using both forward and reverse dosimetry with a view to predicting hepatic toxicity as a part of chemical risk assessment. Ex vivo estimates were well correlated with serum T4 at 4-day exposures but were inconsistent at later timepoints. In the first project, we describe the outcome of a retrospective case study of 448 chemicals with high-throughput predictions of bioactivity, reverse dosimetry, and exposure, as well as traditional hazard information. Together these case studies enable regulatory scientists from different international contexts to develop efficient approaches for chemicals management, while possibly reducing the need for animal studies. Utilizing pluripotent stem cells, in conjunction with high throughput screening technologies, has the potential to aid developmental hazard prioritization for large numbers of chemicals and lessen the strict reliance on costly and time-consuming animal methods. These findings set the stage for identifying and developing new approach methodologies based on in vitro data and in silico models for prenatal developmental toxicity. Basic elements in the ontology are subjects (enzymes, receptors, cell types) and their quantitative relationships (response-response relationships), forming a network of biological interactions to be mapped to a vulnerable developmental window for. Ultimately, this network can be dynamically modeled in silico, providing an integrated computational systems model allowing toxicity predictions at the level of adverse outcomes in the intact individual. A battery of cell-based in vitro assays can be used to monitor the critical rate-determining steps in the network, providing a tiered testing strategy to collect data feeding into the systems model. Integrating the dynamic model with information from exposure and kinetic models allows quantitative hazard and risk assessment while avoiding animal testing. The same data sources are used to train neural networks, resulting in a high level of predictivity. Chemical and biological similarity calculations using the neural networks have also been performed to better understand how these artificial intelligence approaches provide predictions. Most of the models developed using these methodologies predict at accuracy levels above 80%, and a number predict above 90%, showing extremely good performance using holdout cross-validation. Combining these orthogonal in silico approaches provides further confidence in their predictions and a larger impact for computational toxicology. The metric thus gives us the ability to know how accurately we predict the truly unknowns. The diverse phenotypic features and cell lines allow us to detect perturbations to different biological pathways. The Hallmark Gene Sets were originally generated by Liberzon and colleagues to represent defined biological processes and coordinated expression patterns. Changes in gene expression can be used to model the toxic effects of the test article. This can be done by comparing the effects with other substances in other databases and analysis tools. The curation utilized the NextBio platform to identify correlations between Hallmark Gene Sets and genes upregulated or downregulated in rodent liver. The mechanism-based scheme organizes the toxicological data based on the proposed mechanisms of effect and mechanistic data supporting key events leading to each toxicological endpoint, with corroborating epidemiological data providing a bridge to human health effects. In addition, the data are organized into major and minor domains, to assist in characterizing the uncertainty of the relevance of the toxicological data to human health. The evidence is largely driven by weak evidence from the epidemiological literature pertinent to smokeless tobacco use, and toxicological data that can be best classified as minor or supportive in nature. However, it is unclear whether they provide similar performance and reliability in predicting chemical toxicity measurements. While ToxCast data is annotated to include information about technology platform, assay design, and gene target (where appropriate), it remains a challenge to place assay outputs into a toxicological context. To date, 168 ToxCast assay endpoints have been manually mapped to "acute systemic toxicity" by linking them to distinct modes-of-action (MoA) known to be relevant to acute systemic toxicity. Acute systemic toxicity MoAs rich in ToxCast data include mitochondrial inhibition (20 assay endpoints), altered ion flow (23 assay endpoints), and oxidative stress (27 assay endpoints). Likewise, 154 assay endpoints have been mapped to "developmental toxicity", for which MoA groupings include neural crest cell disruption (26 assay endpoints), endocrine disruption (49 assay endpoints), and vascular disruption (23 assay endpoints), among others. To demonstrate the utility of MoA mapping for toxicity outcomes, we present a case study using the ToxPi prioritization approach, which leverages weighted relationships across various MoAs to yield insight into the potential of a chemical to elicit developmental toxicity. A complex suite of approaches is needed to gain insight into biological interactions between test substance and target organism. These approaches include in vitro and ex vivo testing, complemented by in silico model predictions and computational tools to inform the decision process. A new in vitro to in vivo extrapolation tool has expanded functions to address multiple species and metabolism components in both single-compartment and three-compartment physiologically based pharmacokinetic models. A simple machine learning tool allows exploration of data relationships and model building. The chemical characterization and comparison tool helps users describe and investigate their chemical testing space. Integrator improvements simplify data selection and toggling between views, and new data sets have been added, including reproductive and developmental toxicity data. Analysis of groundwater in Gela, Italy revealed significant contamination from a local industrial site. One of the chemical compounds, ethylene dichloride, was found to be present in the highest concentration per legislative allowed value. This study investigates the computational association between ethylene dichloride exposure in Gela and hypospadias.
Thus herbals dario bottineau nd order 30caps himplasia visa, we developed a novel prioritization scheme to select chemicals for screening in biologically-relevant follow-up assays rumi herbals chennai cheap himplasia 30caps on line. Chemicals (558/778 active chemicals) were clustered by structural similarity using ChemoTyper ToxPrint fingerprints herbs philipson buy 30caps himplasia fast delivery. Highly-ranked agonist clusters contain phenols herbs chips cheap himplasia 30caps without a prescription, organochlorine insecticides herbals benefits 30caps himplasia with mastercard, and retinoids herbals for arthritis purchase 30caps himplasia with mastercard. Cytotoxicity contributed significantly to the antagonist priority rank, with as many as 68% of antagonists suspected to be cytotoxic in the active concentration ranges. Here, we further expanded the screening chemical space to the 804 substances in the ToxCast e1K library. Endocrine Disrupting compounds are being increasingly detected in the environment and may have a profound impact on the development and physiology of vertebrate organisms. The zebrafish vertebrate model is broadly used in both human and aquatic toxicity assessment due to their low cost, small size, rapid development, and homology with mammals. Besides, the existence of numerous transgenic strains enables to perform fluorescence-based screening assays with medium throughput. The fluorescence of the reporter gene allows monitoring in vivo the upregulation of the thyroglobulin gene expression as a compensatory reaction to thyroid gland disruption. In this assay, the exposure concentrations of test substances were selected according to the results of a preliminary acute toxicity assay to avoid any interference by non-specific toxicity. Kawamoto, Japanese Society of Toxicology Thyroid follicular cell hypertrophy, hyperplasia and adenoma/carcinoma are often observed in toxicity studies using rodents. In rats, it has been also recognized that males are more susceptible to chemically induced thyroid follicular cell tumors formation than females, but little is known about the details of sex differences in susceptibility on thyroid effects, such as physiological serum hormone levels or thyroid follicular cell proliferation, not to mention the mechanism of the sex differences. We investigated possible sex differences in these thyroid related parameters in rats. This screening methodology showed to be a sensitive and cost-effective assay to evaluate the potential thyroid disruptor activity of chemicals. These assays form part of an in vitro screen used to generate data to study chemical endocrine disruption hazard. The results indicate that T4 glucurono-conjugation capacity and the response to inducers is greater in rat hepatocytes compared to human hepatocytes. Overall this work highlights a need to standardize and validate these in vitro assays if they are to be used in a weight of evidence approach to address species differences in liver mediated thyroid toxicity. In utero, appropriate thyroid hormone concentrations are absolutely required for normal nervous system development. To understand the effect of chemicals on these functions the following assays are utilised. Rat sodium iodide symporter inhibition and rat and human deiodinase 1,2 and 3 inhibition assays are currently being validated. Sur, Endocrine Society Phthalates are plasticizers that have endocrine disrupting effects. Metabolomics provides quantitation and quantification of metabolites (<1000 Da) in a multitude of different physical properties in tissues or body fluids. After euthanasia, testis tissue homogenates were prepared in methanol:water mixture and centrifuged in 1500 rpm for 20 min at -8oC and supernatants were evaporated. We found that metabolites "urea" and "erythrose 4-phosphate" were different among all study groups. Moreover, in high dose group, "urea" and "9,12,15-Z,Z,Zoctadecatrienoic acid" levels were decreased and glucopyranose and pantothenic acid levels were increased vs. In low dose group, 1-hydroxyanthraquinone was increased and octadecanol, cholesterol and erythrose 4-phosphate were decreased vs. The metabolomic difference in high dose versus control was sharper than low dose group. When we compared low dose and high dose groups, L-alanine, hydroxyaspartic acid, octodecanoic acid and L-norleucine levels were increased in high dose group. T-2 toxin, a trichothecene mycotoxin, is a common contaminant in food and animal feed, and is also present in processed cereal products. The most common route of T-2 toxin exposure in humans is through dietary ingestion. The cytotoxic effects of T-2 toxin include modifications to feeding behavior, nervous disorders, cardiovascular alterations, immunosuppression, and hemostatic derangements. In the present study, female Wistar rat were given a single dose of T-2 toxin at 2 mg/kg b. The results showed that pathological lesions were obvious in the brain at three days post-exposure; lesions in the pituitary were not observed until seven days post-exposure. Autophagy in the brain and apoptosis in the pituitary suggest that T-2 toxin may induce different acute reactions in different tissues. Importantly, low concentrations of T-2 toxin in the brain were observed in only one rat. Therefore, given its widespread pollution in food, we should pay more attention to the neurotoxic effects of the T-2 toxin, which may have widespread implications for human health. We applied a semi-quantitative weighting scheme to rank endocrine-responsive endpoints from various toxicity studies according to their relevance for each hypothesized MoA. For each MoA, endpoints sensitive and specific were assigned Rank 1, those sensitive and specific but subject to confounding influences were assigned Rank 2, and Rank 3 comprised endpoints capable only of corroborating higher-ranked results. Data were available for 64 endpoints relevant to E MoAs but only 6/22 Rank 2 and 6/42 Rank 3 responded to benzene. Of data from 64 endpoints relevant to A MoAs, benzene affected only 7/27 Rank 2 and 5/37 Rank 3. Of data from 46 endpoints relevant for T MoAs, only 12/30 Rank 2 and 2/16 Rank 3 responded to benzene. Of data from 69 endpoints relevant to S MoAs, only 6/31 Rank 2 and 8/38 Rank 3 responded to benzene. Across the entire dataset, no endpoint responded consistently but many consistently failed to respond. This underscores that List 2 is not a list of endocrine active or disruptive chemicals. Following a comprehensive literature search within PubMed and Embase databases, followed by hand-searching and evaluation of secondary sources, a total of 21 in vitro and in vivo studies across species were identified for review. In vitro, there was weak or negative activity for T transport protein or activation of E, A or T receptors. This dysregulation of energy homeostasis can cause an increase in susceptibility to metabolic disorders. We recorded body weight, crude food intake, body composition, metabolic rate, locomotor activity, meal patterns, glucose and insulin tolerance, and plasma peptide hormone levels. We are currently processing hypothalamic samples to measure protein and gene expression of anorectic and orexigenic neuropeptides. In the present study, we have investigated the endocrine effects of simulated leachate from a solid waste dumpsite. Overall, the chemical, molecular and physiological data presented herein indicate that the Lemna solid waste dumpsite is a significant source for environmental contaminants with endocrine disruptive potentials, and with overt health consequences for wildlife and human. Given the potential ecological impacts and absence of suitable management procedures for solid wastes in developing countries, our data for immediate litigation approach for sustainable management and environmental protection. To better understand the mechanisms by which maltol regulates melanophore pigment aggregation, we tested if maltol treatment affects hormonal and neural mechanisms known to control melanophore pigment aggregation. To determine if maltol affects camouflage adaptation, we placed tadpoles into maltol baths that were situated over either white or black background. Maltol induced pigment aggregation in a similar dose-dependent pattern regardless of background color. We also tested how maltol treatment compares to melatonin and found that the degree of pigment aggregation induced by maltol is similar to treatment with melatonin, but the time course differs significantly. Melatonin induced pigment aggregation within minutes, whereas maltol induced aggregation over the course of several days. Ongoing experiments are examining the effects of pinealectomy on how maltol affects melanophore pigment aggregation. Thus, maltol may regulate pigment aggregation via a retinal-based mechanism; ongoing experiments are addressing this issue. These results are the first to describe the impact maltol has on melanophore biology and demonstrate that melanophores can be a valuable endpoint for screening compounds for a variety of hormonal and neural mechanisms. Ingestions of plastic microbeads have been identified in different aquatic organisms globally. Potential acute toxicity of ingested microbeads could be characterized as physical effects including blockage of digestive system or biological effects linked to alterations in oogenesis process and detoxification processes. Adult zebrafish was used as model organisms because of its fully characterized genome and evolutionarily conserved behavioral responses. All concentrations used are relevant to the environmental concentrations found in local waters. Zebrafish behaviors were recorded by video and two observers (interrater reliability > 85 %). In addition, 60 % and 30 % of fish ingested and retained with microbeads in intestine (medium and high concentration) and gills (high concentration). In summary, effects on aryl hydrocarbon receptor (AhR) pathway, disruption of oogenesis process and neurotoxicity in adult zebrafish could be caused by acute exposure to microbeads. Gravid adult worms were synchronized and embryos were stored in M9 buffer 18-21 hours until hatching. Plates for the osmotic avoidance assay contained a 2 centimeter diameter ring of 4M fructose in 1% congo red. Five nematodes were placed in the center of the ring, and the number of worms leaving the ring, touching the ring, or staying in the ring was recorded at 5 and 10 minute intervals. Worms that leave the ring are considered to display abnormal avoidance behavior indicative of sensory deficits. Information on the effects of exposure to mixtures of toxic substances is urgently required, however. Alternative toxicity models have the potential to provide relevant data for human safety assessment of chemicals with rapid turnaround times and at greatly reduced cost relative to traditional methods. Caenorhabditis elegans is a small nematode with a 3-day lifecycle that can be easily maintained in axenic liquid media using standard laboratory techniques. Many pathways involved in organismal development and neurotransmission are conserved from worms to people. Arsenic, lead, and mercury are mammalian developmental neurotoxins that have been associated with hyperactivity in children. One concern in mixtures risk evaluation is the in vivo occurrence of synergistic effects not predicted by in vitro testing or in silico analyses. Binary mixtures of arsenic, lead, and mercury produced equivalent or additive effects on developmental delay and/or hyperactivity, however no synergistic effects were detected. Persistent drought conditions and increased nutrient water pollution run off perpetuate the public health risk of microcystin-producing harmful algal blooms. Recent studies have highlighted the reproductive system as an additional target organ. Furthermore, multigenerational studies in mammals and aquatic animals looking at the offspring of exposed parents have demonstrated changes in the F1 generation, including altered neurodevelopment, growth, and oxidative stress markers. Epigenetic histone modifications, including H3S10p and H3K9me3, in the germline are evaluated using immunofluorescence, germline stress is monitored through desilencing via loss of repressive histone regulation, and germline and somatic cell toxicity is evaluated through apoptotic, growth, and behavioral endpoints. Treatment was performed by subcutaneous microinjection of 10 L test chemical into the front pro-leg. Methylmercury (MeHg) is a ubiquitous environmental toxicant that is conventionally known to target developing neural tissue. Hallmarks of developmental MeHg toxicity include permanent cognitive and motor impairments. It was previously indicated in Drosophila embryos and pupa that MeHg upregulates the Notch-responsive gene, E(Spl)m, suggesting that MeHg may perturb the coordination of early neurogenic and myogenic events mediated by Notch signaling. Additionally, a recent genome wide association study in Drosophila for developmental sensitivity to MeHg implicated several myogenic gene candidates. Among these candidates was kon-tiki (kon), which encodes a cell-adhesion protein that is required for muscle-tendon attachment initiation. To address this hypothesis, we evaluated morphological and functional phenotypes following larval exposure to increasing concentrations of MeHg. While eclosion was significantly reduced at higher doses of MeHg (10-15uM), lower doses (2-5uM MeHg) showed deficits in flight behavior. The morphological and functional defects imparted by developmental exposure to MeHg are consistent with a failure in muscle-tendon attachment, and furthermore suggest that kon may mediate this effect. Atrazine, a triazine herbicide, is one of the widely used herbicides in the United States and many other countries. Several epidemiological studies have associated atrazine (herbicide) exposure with increased incidence of type 2 diabetes (T2D), which accounts for more than 90% diabetic cases. Finally, this study not only provided experimental evidence to the epidemiological propositions on the diabetogenic potential of atrazine but also highlighted the potential of Drosophila as a model for deciphering the mechanisms underlying xenobiotic mediated onset of type 2 diabetes. As a consequence of their increased use, understanding potential adverse outcomes following exposure to cannabinoids during critical developmental periods is important. Zebrafish were waterborne exposed from 5 hours post fertilization (hpf) through the larval stage (96 hpf) to 0.
After years of tissue development herbs nyc proven himplasia 30 caps, the final hurdle for the round robin validation study using reconstructed human epidermis (RhE) tissues for medical devices was the development of extractable controls equine herbals buy cheap himplasia 30 caps on line. Previous RhE/medical device feasibility studies were completed without irritant polymers herbals that reduce inflammation 30caps himplasia visa, so for the round robin study herbals2go discount 30 caps himplasia visa, positive control materials were created by infusing polymers with known irritants herbals to lower blood pressure purchase himplasia 30 caps on-line. In order to successfully incorporate hydrophilic and hydrophobic irritant chemicals wtf herbals generic 30caps himplasia with mastercard, a variety of medical device polymers were investigated. The final four polymer-releasing irritants were chosen based on their irritation potential, octanol/water partition coefficient, miscibility with polymer matrices, and use in the medical industry. Verification was performed through extraction and chemical analysis, along with RhE tissue irritation testing prior to their inclusion in the round robin validation study. In this presentation, we will discuss the development of the four novel compounds through unique mixing and curing methods, the challenges encountered during development including the various irritants, concentrations, mixing, and curing processes executed to determine the amount needed to elicit an appropriate irritant response without destabilizing the polymers, and the variety of irritants that were trialed. W 1637 A Tale of an In Vitro Method: From Inception to International and Regulatory Acceptance A. In vitro alternative test methods sound promising but can often be difficult to implement on a global scale in a way that will be truly impactful. Every medical device, irrespective of its nature or body contact, must be assessed for its potential to cause cytotoxicity, irritation, and sensitization. It seemed logical that this method, with a few adjustments, could also be used to assess medical device extracts. Introducing this test as the preferred method to address the irritation potential of medical devices will greatly reduce the number of animals used for the biological safety assessment of medical devices and combination products prior to market release. This session will present the monumental collaboration that took place to bring the in vitro irritation method for medical devices to the industry, including manufacturing an extractable positive control, designing and performing an international interlaboratory round-robin study, and presenting of tools to fast-track the method into regulatory acceptance. W 1641 the Application of Reconstructed Human Epidermis (RhE) Models as In Vitro Skin Irritation Tests for Detection of Irritant Activity in Medical Device Extracts W. Turley Assessment of skin irritation is an essential component of the safety evaluation of medical devices. An international round robin study was conducted to evaluate the RhE method for determination of skin irritant potential of medical device extracts. Four irritant polymers and three non-irritant controls were obtained or developed that had demonstrated their suitability to act as positive or negative test samples. Our results indicate that RhE tissue models can detect the presence of strong skin irritants at low levels in dilute medical device polymer extracts. Therefore, these models may be suitable replacements for the rabbit skin irritation test to support the biological evaluation of medical devices. These standards address animal welfare, materials characterization, toxicity testing, risk assessment and other issues surrounding biocompatibility assessment of medical devices. Skin irritation is a biological effect that must be considered for virtually every medical device regardless of its type or duration of body contact. Historically, the Draize rabbit skin irritation test has been used to evaluate the irritation potential of chemicals. The rabbit test is considered the gold standard for medical device irritation assessment; however, it has some shortcomings. This process involves chemical characterization, toxicological risk assessment, and, if necessary, biological testing. All medical devices, at a minimum, need to be evaluated for their potential to cause cytotoxicity, sensitization, and irritation. Cytotoxicity is an in vitro test; however, sensitization and irritation are still performed in vivo, which results in a large number of animals being used annually. There is a growing movement in the medical device industry to reduce in vivo testing by adopting in vitro alternatives. Over the past decade other industries have replaced animal-based irritation testing with human tissue-based in vitro methods. Tool categories include biomarker tests, clinical outcome assessments (such as clinician reported rating scales), and non-clinical assessment models (such as in vitro models to replace animal tests). The qualification process for in vitro irritation testing will be used as a case study with attention given to the practical questions of cost and protocol ownership. Two of the most commonly occurring human birth defects are hypospadias of the phallus and cryptorchidism of one or both testes. Further, reductions in adult sperm counts have been reported in multiple countries. Increases in the prevalence rates of these disorders over the past several decades have been reported and exposure to environmental chemicals has been suggested as a causal factor. A variety of environmental chemicals that operate via a range of molecular mechanisms have been shown to produce male reproductive tract disorders following in utero exposures in laboratory animal experiments. An underlying hypothesis of these mixtures studies is that although the chemicals target different molecular initiating events, their convergence at critical key events will ultimately lead to dose additive adverse effects when exposure occurs as a complex mixture. Results indicate that, despite acting through disparate molecular mechanisms, chemicals impacting male reproductive development act cumulatively to produce adverse effects similar to those observed in human populations. W 1643 Applying Systems Biology Approaches to Understand the Joint Action of Chemical and Nonchemical Stressors C. Toxicology has evolved from a strictly observational science to a more predictive one that relies on knowledge of stressors (chemical or nonchemical) and the biological systems with which those stressors interact to identify health hazards. Furthermore, the introduction of the exposome concept brought into sharp focus the fact that humans are routinely exposed to a great number of chemical and nonchemical stressors over the course of a lifetime. Chemical stressors can arise from everyday use of personal care products and consumer products, occupational exposures, and exposure to pollutants through contaminated air, water, and/or food. The traditional reductionist view reflected in toxicology by the study of one chemical at a time falls short of the promise of high-throughput technologies, a focus on biological pathway disruption, and acknowledgement that real-world exposures are complex. In response to the evolution of our thinking in toxicology and exposure science, a rational approach to address the challenges of mixtures has emerged. Mixtures toxicology refers here to predictive models of how stressors can act when they are present concurrently, exemplified by concepts of dose addition and response addition. The starting place of this conceptual framework is the disease or endpoint of interest. Next, the adverse outcome pathways that converge at that disease are described as a network of intersecting pathways that lead from multiple molecular initiating events or key events to a single apical target. Chemicals or nonchemical stressors that are known to disrupt those pathways are identified. Finally, we can develop and test hypotheses of how those stressors might contribute to development of the disease or adverse outcome of interest. Recently, several independent groups have developed projects or case studies to work through this conceptual framework. Examples of endpoints include disruption of male reproductive tract development, atherosclerosis, steatosis, and cancer. Although these efforts are in various stages of development, a detailed review of the available programs will provide opportunities to identify challenges and knowledge gaps, share information, and foster collaboration and cooperation to move the field forward. Case studies, such as the ones presented here, will inform cumulative risk assessment by providing a path forward for determining which stressors to include and how we might move away from a chemical-centric perspective to one focused on the diseases that are of greatest concern to public health. W 1646 A Model Disease to Determine the Interaction of Chemical and Nonchemical Stressors D. A critical research area which requires further exploration is the biological mechanisms and effects of exposure to both environmental chemicals. Approaches and research needs include: characterizing qualitative and quantitative impacts of exposure to the combination of chemical and non-chemical stressors, developing new models and methods for assessing the toxicity of multiple co-occurring environmental hazards, and analyzing the effects associated with susceptible and vulnerable populations. Research surrounding systems-level effects of chemical and nonchemical stressors has expanded over recent years, alongside the increasing feasibility of multi-target and -omic-based investigations. Databases relevant to systems biology have also grown, serving as central repositories for toxicological response information that can be leveraged to better understand molecular events resulting from multiple stressors. What remains underdeveloped are methods to effectively relate such data to individual disease phenotypes. Recent progress has been made through the implementation of organizational schemes, including Adverse Outcome Pathways and the Ten Key Characteristics of Carcinogens. These recent advances will be discussed alongside examples of how chemical-induced biological pathway perturbations have been related to disease outcomes, while highlighting the current data gaps and limitations in tools available to understand systems-level effects of chemical and nonchemical stressors. The EuroMix approach includes prioritization of chemicals based on in silico predictions and binning of chemicals into cumulative assessment groups based on mode of action and/or adverse outcomes. Different food relevant compound mixtures have been tested and an in vivo proof of concept experiment was performed. The results demonstrate the suitability of the in vitro toolbox for liver steatosis to assess mixtures with a similar or dissimilar MoA. W 1650 Early Screening for Nephrotoxicity Employing Transporter Overexpression Cell Lines S. Nephrotoxicity due to drugs and environmental chemicals accounts for significant patient mortality and morbidity. The proximal tubule is of particular interest due to its active clearance, reabsorption and intracellular concentration. In this presentation the current status for proximal tubule toxicity screening will be discussed. However, cells commonly used in in vitro toxicity studies lack transporter expression which can lead to false negative results. These results demonstrate the utility of using transporter over expression cell line to help understand the mechanism of toxicity and potential use as a screening tool. The Hallmarks of Cancer described by Hanahan and Weinberg represent the biological pathways that are critical in cancer development. The ten Hallmarks are not discrete events, but interrelated cellular processes that are perturbed in carcinogenesis. The Halifax Project used the Hallmarks of Cancer as a starting place to develop a hypothesis for the effects of environmental mixtures on cancer development. Through this effort, cancer biologists and environmental scientists were brought together to discuss the role of chemical mixtures in cancer development and progression. The hypothesis was nominated by the Environmental Working Group to the National Toxicology Program to stimulate research on the role of environmental mixtures in cancer. This presentation will highlight the conceptual development of a testing program to address the convergence of environmental chemicals on the network of pathways involved in cancer development. For example, the angiogenesis Hallmark will be discussed in terms of environmental chemicals that have been implicated at inducing angiogenesis and in vitro screening tools that could be used to evaluate candidate chemicals for inclusion in the program. The application of in silico approaches to combine multiple pathways and predict the joint effects of chemicals that target the Hallmark pathways will be discussed. Lu Direct reprogramming by forced expression of transcription factors can generate desired cell types from differentiated cells without the prior induction of pluripotency. While directly reprogrammed tubule cells offer a potential road to regenerative approaches, a more tangible goal is their use in disease modeling and toxicity screening. Therefore, direct reprogramming may be an attractive in vitro strategy to advance patient specific nephrotoxicity testing. Lu the general aim of the NephroTube Challenge is to develop a multi-compartmental microfluidic device that models renal tubular injury observed in nephrotoxicity. This demands a triad of 1) a human renal cell line with intact renal transporter function and metabolic activity, 2) sophisticated microfluidics compatible with high-throughput analysis, and 3) high level expertise in toxicology. Developing and implementation of such device has the potential to reduce animal experimentation and improve predictivity of drug-induced kidney injury during drug development. Our kidney-on-a-chip device was exposed to twelve compounds known for their nephrotoxic potential (including cisplatin, tenofovir, tobramycin and cyclosporin A) for 24 and 48h. Inter-laboratory variation was limited and robustness of the cell-based assays could be demonstrated. Further validation using chemical compound libraries and implementation in drug development is required to demonstrate the value of such models to reduce animal experiments and improve drug safety. Active renal secretion in the proximal tubules is a major drug elimination route, making the kidney susceptible to drug-induced injury. High blood flow to the kidneys significantly contributes to exposure to potential nephrotoxins that enter the cells mostly basolaterally via organic anion and organic cation transporters or apically via reabsorption processes. Many drugs associated with proximal tubule damage are polar, such as acyclovir (cLogP -2. To investigate the nephrotoxic potential of lead compounds, in vitro systems should emulate the renal physiologic environment, including functional transport machinery. Cell lines or primary cells traditionally used in 2D kidney toxicity screening lack the appropriate transporter expression, in vivo structure, and function and are unable to predict preclinical/clinical kidney toxicity. Recent biotechnological developments provide more sophisticated and promising models, including 3D culture platforms and reprogrammed proximal tubule cells, which could be utilized to create a more physiologically relevant platform with the potential to improve the prediction value for proximal tubule toxicity screening. The session will provide a general overview of these state-of-the-art biotechnological advances to facilitate the discussion about the path forward for in vitro kidney toxicity screening with high reliability and mechanistic insight. Polymyxins are potent antibiotics but their use is restricted because of nephrotoxicity. To mitigate nephrotoxicity, structural analogues of polymyxins are being developed. Transcriptional profiling identified cholesterol biosynthesis as the primary pathway induced by polymyxin B. Inhalation of respirable crystalline silica leads to development of silicosis, a progressive pneumoconiosis associated with autoimmune disease, increased tuberculosis and lung cancer. About 2 million workers are exposed to silica in the United States but no specific therapy is available. The first line of defense against silica is innate immunity: macrophages filled with silica particles generate reactive oxygen species and secrete cytokines, leading to cell death that contributes to silica-induced lung disease.
Rankly ground should be put under cultivation before being again used for clover or grass herbals dictionary order 30caps himplasia amex. Good drainage is an assistance in subduing this weed lotus herbals order 30 caps himplasia amex, for it likes the soil to be moist wholesale herbs buy cheap himplasia 30 caps line. It is not applied to the insistently a water- weed herbals for anxiety buy 30caps himplasia amex, as its name implies herbalsondemandcom purchase himplasia 30caps visa, but will grow where the soil is only moderately moist herbs mopar himplasia 30caps line. Achenes minutely ridged, lens-shaped or three-angled approaching to ovoid, dull, reddish brown. Range: New Brunswick to Minnesota, southward to Florida Mexico also in California. Stems slender, erect or decumbent, one to three feet long, usually simple or with a few branches near the top, smooth or with appressed, bristly hairs. Leaves narrowly lance-shaped, acute, bristly-hairy on the midribs sheathing stipules beneath, ciliate, not glandular, and not acrid narrow and bristle-fringed. Spikes terminal, erect, narrow, often interrupted below calyx pink or greenish white, with eight stamens and with style deeply three-parted. Polygonum Other English names: Spotted Smartweed, Spotted Knotweed, Red-shanks, Heartweed, Peach-leaved Persicary. Range: Throughout the American Continent except the extreme North, and in most parts of the world. The seeds of this weed form one of the most common impurities of commercial seeds, particularly of red clover. In a bulletin issued by the Agricultural Experiment Station of Nevada, concerning "Clover Seeds and their Impurities," it is stated that of red clover samples submitted for inspection (obtained in all parts of the country), 62. Leaves lance-shaped, smooth or with fine hair roughening the edges, pointed at both ends and generally blotched near the center with a large brownish spot. Flowerspikes numerous, dense, erect, a half-inch to two inches long; calyx pink or purplish with four or five obtuse lobes, usually Achenes lenssix stamens, and a two- or three-parted style. In some localities the plant is said to harbor the corn-root aphis, the louse appearing with the first leaves. Even so expensive a process as is often worth the labor if it hinders so pernicious a weed as this from fouling the ground with its long-lived seeds. In grasslands and grain fields a spray of four-per-cent solution of Copper sulfate will greatly damage the foliage of the weed, checking growth and usually blasting the budding flowers. Not very troublesome in ground re- quiring close tillage, but a special nuisance ingrain fields; climbing over and strangling the rightful growth, robbing it of food and moisture, bending of its it down by weight seeds have long vitality and begin to ripen and drop into fruitage. Directly after harvest induce germination of seeds on the ground by giving surface cultivation, the resulting growth being winter-killed or turned under by the plow. A very conspicuous weed, especially when in fruit, capable of spreading itself over a square rod or so of ground, when not finding other support. Stems very slender, pale green, faintly ridged and slightly roughened on the ridges, three to twenty feet in length; several such stems strike off in all directions from the deep-boring, branching, perennial root. Leaves halberd-shaped, the tips and the basal auricles rather long-pointed, smooth but with edges slightly roughened petioles long and nearly as thick as the stem from which they spring sheath smooth, oblique, slightly rough on the ridges. Flowers yellowish green, in slender, axillary racemes, interrupted and leafy, two to four inches long calyx five-parted, the three outer segments winged and decurrent on the pedicels. Otherwise cut the vines from the roots while in early flower, using salt or kerosene on the shorn surfaces. Vines like this are an argument against any more fences than are absolutely necessary. Leaves one to three inches long, lance-shaped, with wavy and irregular but sharp teeth, narrowing at base to short, slim petioles when young they are pale green, but they usually turn dark purple as the plant matures. Flowers in loosely spreading, interrupted panicles, very small, sessile, and scattered unevenly on the spikes calyx urn-shaped, with five pointed lobes, keeled and curved inward, around the base of which develops a thin, membranous, horizontal wing, or border stamens five styles three Seed flattened and horizontal, crustaor occasionally two. Stragglers of roadsides Maturing and waste may land should receive attention, for a few tumblers from such sources seed a wide area. It is becoming increasingly common, particularly on the prairies, where the winds it far on the unrestricted levels, for rounded, compact growth makes it a tumbleweed. Its name of "Mexican fireweed" is a misnomer, for it is an immigrant carry its from Europe. In autumn the dense foliage turns fiery red, but later linear,; the plants become brown and. Leaves oblong to lance-shaped, one to three inches long, smooth, wavy-toothed or nearly entire, especially the upper ones, which are pointed at both ends and sessile or with very short petioles. Both plants are used in medicine as anthelmintics, and the seeds, from which the essential oil is usually distilled, are salable in the drug market for six to eight cents a pound. Turnpike Geranium indicates the fondness of this where it is usually an unsightly object, with its glandular, hairy leaves and flowers overlaid with dust. It is strong-scented, with an odor somewhat like turpentine, and grazing animals, even sheep, usually leave it alone. Stem eight inches to two feet tall, slender, erect, simple or with very few branches, green, glandular-hairy, and viscid. Leaves obIts name of weed for the public road, long, pinnately lobed, obtuse at apex, the lobes also obtuse with petioles slender, short, the upper leaves becoming Flowers in spreading, cyme-like racemes, small, green, calyx-lobes pointed, hairy, not quite coverviscid, very numerous crenate teeth sessile. Range: Nova Scotia to Alaska, southward to New Jersey, Illinois, and Minnesota, and in the Rocky Mountains to Colorado, Utah, and Nevada. Leaves triangular or halberd-shaped, one to three inches long, thin, pale green, irregularly and coarsely toothed, not mealy petioles slender, the lower ones about as long as the blades. Means of control Prevent seed production either by hand-pulling or by close cutting while in bloom. Like the White Goosefoot, this plant has accompanied the settler to every part of the world. Stem eight to twenty inches high, rather stout,- grooved, succulent, with numerous spreading branches, the lowermost often prostrate on the ground, glaucous, often mealy. Leaves oblong to lance-shaped, wavytoothed or partly pinnatifid, the lower ones obtuse at apex and tapering to a slender petiole, the upper ones acute, often entire, sessile or nearly so, pale green above and white-mealy beneath. Flowers in small axillary clusters, usually not so long as the leaves, crowded on. Seed dark brown, flattened, sharp-edged, the utricle having its summit not completely cov- European ered by the Means of calyx. Range: Quebec to tbe Northwest Territory and British Columbia, southward to Pennsylvania, Ohio, Kentucky, Kansas, Utah, and New Mexico. Habitat: Open woods and thickets, farmyards, roadsides, waste places a frequent tenant of city vacant lots. Leaves smooth, thin, deep green, not mealy, the lower ones sometimes four inches long, ovate, long-pointed, with one to four large, pointed teeth on each side, the base truncate or rounded, petioles rather long and slender; the upper leaves lance-shaped, usually entire. Flowers in large, loosely spreading, terminal and axillary panicles calyx green, its five lobes keeled, rather obtuse, not wholly covering the seed, which is sharp-edged. A succulent, swift-growing weed, which rapidly absorbs the food and moisture needed by the crops among which it intrudes. The stem sometimes attains to six feet, but is usually two to four feet tall, stout, erect, ridged and grooved, much branched, often striped with pink or purple, growing from a short, stout main root with many branching rootlets. Leaves rhombicovate or goosefoot-shaped near the base, but become more narrow and lanceshaped as they ascend the stem until those near the top are often nearly linear; smooth and green above but often covered on the under side with a when young, ones irregularly cut and toothed, with petioles often as long as the blades. Flowers small, green, crowded on spiked panicles in the axils and at the summit of stem and branches calyx secretion, especially mealy the lower; and enfolding the seed, which is lens-shaped, small and black; these seeds have very long vitality, lying dormant in the soil for years and germinating when brought near the surface by cultivation. In gardens and other small areas, it should be hoe-cut or hand-pulled while young. Stem ten to twenty inches high, leafy to the top, slender, often decumbent, sometimes erect, usually loosely branched. Leaves rhombic-ovate, thin, green on both sides, with large, coarse, wavy but sharply pointed teeth, bases broadly wedge-shaped, truncate, or slightly rounded, with petioles shorter than the blades. Panicles in small, branching, divergent, somewhat corymbose clusters, axillary, and shorter than the leaves calyx-lobes not wholly enclosing the seed, which is sharp-edged and very flat. Range: Nova Scotia and Ontario to New Jersey and Ohio also in northwestern United States and British Columbia, where it is; probably native. Smooth Pigweed and ranking with it in weedy Stem one to three feet in length, prostrate or ascending five inches in length, long- or sometimes erect, diffusely branching, grooved, often with reddish stripes. It is stouter, more erect, the leaves broadly halberd-shaped and often coarsely and irregularly toothed, particularly the lower ones, the petioles often as long as the blades. Means of control is; causes the stems to stool freely, and the the best remedy cutting new growth hastens to mature fruit, requiring attention a second time; so that prompt uprooting saves trouble in the end. In cultivated crops these plants give little trouble, for there they are usually destroyed as seedlings. Range: Shores of the Great Lakes to the Time British Columbia, southward to Missouri, Texas, Habitat: Dry, sandy soil; grain fields, hoed crops, Northwest Territory and and Arizona. This is another of the plants that often become tumbleweeds when mature, which explains why its range extends from the Gulf of Mexico to the Arctic Circle. Lower leaves alternate, narrowly linear but rather thick, with the base somewhat dilated, one-nerved, sessile, spreading, a half-inch to two inches long, tipped with a hard, rigid point (cuspidate); the upper, floral leaves, or bracts, are very more than a quarterinch long, with dry, scarious margins. In the axils of these reduced leaves are the solitary flowers, hardly an eighth of an inch long the calyx consists of one delicate sepal, rarely a second one stadifferent, being thinner, ovate, pointed, little; mens one Seed oval, somewhat flattened, with a winged margin, the two persistent styles extended like antennae, completing its likeness to a small bug. Burn over infested ground where plants have matured, in order to destroy seeds on the surface. Seed-time: Earliest flowers mature as early as September, later ones clinging to the plant until nearly springtime. Range: Ontario and Manitoba to Idaho; nearly throughout the in Kansas, Nebraska, and Colorado locally Mississippi Valley;; in Eastern States. A most pernicious weed, which was brought to this country in impure flax seed from Russia not many years ago, but its range is already large and is steadily increasing. Because of its excessive prickliness, the it Dakota farmers who; first made its acquaintance but it is neither, being a Saltwort called and a member of the Goosefoot Family. The young stalks are tender and succulent, the young leaves an inch or two long with young branchlets in their axils at this stage of growth the plant is good forage which cattle and sheep eat greedily. But with the approach of summer weather the plants change their character the stem becomes hard and woody, two to three feet high, ridged, and streaked with red lines, diffusely branched and spreading broadly, crowding to death all;: lesser fall growth. The first leaves those of later growth are not more than a half-inch away; long, mere awl-like spines slightly Russian Thistle (Salsola. Seed very small,; reddish in color, irregular in fine shape but somewhat like a flattened top, held in place by tufts of coiled hair at the base of the persistent calyx, so that only the ripest will fall when the plant is broken from its hold on the soil and sent tumbling before the wind but they continue to ripen and shake loose all winter as the weeds are trundled about. According to the size attained, a thrifty plant may bear ten thousand to a hundred thousand seeds, which retain their vitality in; the soil for several seasons. Young seedlings, six or eight inches high, may be plowed under, a dragchain being used to help pull them beneath the turning furrow. On such land, plowed as late as July, a soiling crop of corn or rape may be grown. In such cultivated crops as potatoes, corn, and beets, tillage should be continued later than is customary. In grain fields, particularly those harvested with a header, the stubbles should be burned over, first being mowed and dried for a few days if the weeds are still green. Entire communities should be concerned in keeping highways, firebreaks, and all waste land clean of Sow clean weed is cut close to the the pest. Leaves petioles, sparsely toothed or alternate, lance-shaped, with short wavy-edged, the upper ones entire. When mature, the stems, bracts, and calyx lobes turn white, and the plants are then very conspicuous. They frequently become tumbleweeds, the woody, brittle stems breaking at the base and the whole weed rolling away before the wind, sowing seed as it goes; by persistently this means its range is being very rapidly extended. Means of control fields, In grain seedlings large numbers of the young be dragged out with a weeding harrow, in the spring, when the crop is but a few inches high; plants that survive this treatment should be hand-pulled later, but before their rank growth injures the crop by absorbing infested. Plants along roadsides and railways and in waste places should be cut while in early flower, shall mature. Stem feet stout, tough, erect, green, rough-hairy, much branched, occasionally attaining a height of ten feet, but usually one to six from a long, with pink or white rootlets. Leaves long tall, springing fleshy, red taproot, befringed ovate or rhombic-ovate, three to six inches in length, dull green, roughhairy, with long petioles and promiFlowers on nent ribs and veins. Each flower produces but one oval, flattened, jet-black, and shining seed stamens; which readily falls from its place when ripe. If they are nearing maturity, remove the plants from the ground, for In grain fields, seedlings seeds will ripen on the stout stalks. Or rater, but before the weed blooms or the grain begins to head, spray with Iron or Copper may sulfate. Range: Throughout North America except the far North; common in the plains regions of the West. Leaves smooth, pale green, a halfinch to two inches long, spatulate, with rounded apex, the midvein extended as a minute bristle; slender, paler than the Flowers in small axillary clusters, green, with three membranous sepals and as many stamens, the three subtending bracts much petioles blades. When the plants mature the leaves fall away, the hardened stems bend inward, the stalk is uprooted lateral ones smaller or;. Destroy by hoe-cutting while young tillage of cultivated crops should be long continued, in order to capture late-ripening plants. Like the other, it crowds out better plants and absorbs much food the and moisture from the soil. Range: Massachusetts to Michigan, Illinois, and Kansas, southward to the Gulf of Mexico. A native of tropical America and a very common and troublesome weed, particularly in the Southern States. Stem one to four feet tall, stout, grooved, erect, smooth, branching and bushy, dark green or often purplish - Leaves one to three inches long, broadly lance-shaped, pointed at both ends, the lower ones with long petioles at the base of each leaf is a pair of diverging stipular spines, one-fourth to one-half inch long, rigid, keen as awls.
